US20050124788A1 - Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production - Google Patents
Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production Download PDFInfo
- Publication number
- US20050124788A1 US20050124788A1 US10/500,047 US50004705A US2005124788A1 US 20050124788 A1 US20050124788 A1 US 20050124788A1 US 50004705 A US50004705 A US 50004705A US 2005124788 A1 US2005124788 A1 US 2005124788A1
- Authority
- US
- United States
- Prior art keywords
- boc
- 4clphe
- heptapeptide
- 3pal
- lys
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims description 24
- 230000008569 process Effects 0.000 title claims description 22
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 title claims description 18
- 239000002474 gonadorelin antagonist Substances 0.000 title claims description 12
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 230000015572 biosynthetic process Effects 0.000 title abstract description 13
- 238000003786 synthesis reaction Methods 0.000 title abstract description 11
- 239000000543 intermediate Substances 0.000 title abstract description 9
- 230000008878 coupling Effects 0.000 claims abstract description 7
- 238000010168 coupling process Methods 0.000 claims abstract description 7
- 238000005859 coupling reaction Methods 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 150000001413 amino acids Chemical class 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 7
- -1 Boc group Chemical group 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 4
- URKWHOVNPHQQTM-OAHLLOKOSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-naphthalen-2-ylpropanoic acid Chemical compound C1=CC=CC2=CC(C[C@@H](NC(=O)OC(C)(C)C)C(O)=O)=CC=C21 URKWHOVNPHQQTM-OAHLLOKOSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims 5
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical class C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000010511 deprotection reaction Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VIHYIVKEECZGOU-UHFFFAOYSA-N N-acetylimidazole Chemical compound CC(=O)N1C=CN=C1 VIHYIVKEECZGOU-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 230000021736 acetylation Effects 0.000 description 5
- 238000006640 acetylation reaction Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000010791 quenching Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 3
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 3
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 3
- 102000009151 Luteinizing Hormone Human genes 0.000 description 3
- 108010073521 Luteinizing Hormone Proteins 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940028334 follicle stimulating hormone Drugs 0.000 description 3
- 229940040129 luteinizing hormone Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 2
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 108700012941 GNRH1 Proteins 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
Definitions
- the present invention relates to intermediates for the synthesis of LHRH antagonists, to a process for the production of these intermediates and to a process for the production of LHRH antagonists.
- LHRH The luteinizing hormone-releasing hormone, LHRH, controls the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH).
- LHRH antagonists are compounds capable of blocking the secretion of FSH and LH. They are generally nona- and decapeptides (but may be shorter or longer) comprising part of or the entire structure of LHRH in which one or several amino acids have been exchanged for other natural amino acids and/or amino acids not found in nature.
- Synthetic LHRH antagonists may be used for contraception and in the treatment of benign hyperplasia of the prostate gland, hormonal-dependent tumors of the breast and ovaries, dysmenorrhea, endometriosis, and other conditions.
- These synthetic LHRH antagonists have the general formula Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-X—NH 2 , wherein X is from 5 to 6 natural and/or synthetic amino acid residues.
- X is AA1-AA2-Leu-AA3-Pro-D-Ala, in particular wherein AA1 is a natural or synthetic amino acid and AA2 is a natural or synthetic amino acid or zero, AA3 is a natural or synthetic amino acid.
- a synthesis strategy disclosed in U.S. Pat. No. 5,710,246 for making decapeptide or nonapeptide LHRH antagonists comprises the coupling of an intermediate tripeptide representing amino residues 1 to 3 (counting starts at the amino terminal of the peptide) with a heptapeptide or a hexapeptide, respectively representing amino acid residues 4-10 and 4-9, respectively.
- the intermediate tripeptide disclosed in U.S. Pat. No. 5,710,246 A is an ester, Boc-D-2Nal-D-4ClPhe-D-3Pal-O-Me or the corresponding benzyl or allyl ester.
- a tripeptide representing amino acids 1-3 of an LHRH antagonist the terminal amino group of which is Boc- or Ac-protected and the terminal carboxyl group of which (that is, the terminal group of amino acid no. 3) is not protected.
- the tripeptide (I) in the synthesis of a peptide of the general formula (IIa) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-AA1-AA2-Leu-Lys(iPr)-Pro-D-Ala-NH 2 (IIa), wherein AA1 and AA2 have the meaning given above, in particular a LHRH antagonist of the formula (III) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Lys(Nic)-Leu-Lys(iPr)-Pro-D-Ala-NH 2 (III) or, even more preferred, of the formula (IIIa) Ac-D-2Nal-D-4ClPhe-D-3Pal-Ser-MeTyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH 2 (IIIa).
- the process of the invention for preparing a LHRH antagonist comprises the step of coupling the tripeptide (I) with a heptapeptide (IV) of the general formula P 1 -Ser(P 2 )-AA1-AA2-Leu-Lys(iPr,P 4 )-Pro-D-AlaNH 2 (IV), wherein P 4 is H or an amino protecting group such as Boc, wherein AA1 and AA2 have the aforementioned meaning, in particular with a heptapeptide (V) of the general formula P 1 -Ser(P 2 )-NMeTyr(P 3 )-D-Lys(Nic)-Leu-Lys(iPr, P 4 )-Pro-D-AlaNH 2 (V), wherein P 1 is selected from H or amino protecting group and P 2 and P 3 are independently selected from H and —OH protecting group, and P 4 has the meaning given above, for preparing the LHRH antagonist Ac-D-2Nal-D-4Cl
- the heptapeptide (V) is described in U.S. Pat. No. 5,710,246 A.
- the heptapeptide of the general formula (IV) including the heptapeptide (Va) can be synthesized by routine modifications of the synthesis of (V) or by coupling the corresponding Boc-amino acids on a peptide synthesizer (Beckman Model 990), as described in WO 94/40757 where also the LHRH antagonist (III) is disclosed.
- the process of the invention for preparing a LHRH antagonist comprises the step of coupling the tripeptide (IX) Boc-D-2Nal-D-4ClPhe-D-3Pal—OH (IX) with a heptapeptide (IV) of the general formula P 1 -Ser(P 2 )-AA1-AA2-Leu-Lys(iPr, P 4 )-Pro-D-AlaNH 2 (IV), wherein P 1 , P 2 , P 4 , AA1 and AA2 have the meaning given above, in particular with a heptapeptide (V) of the general formula P 1 -Ser(P 2 )-NMeTyr(P 3 )-D-Lys(Nic)-Leu-Lys(iPr, P 4 )-Pro-D-AlaNH 2 (V) or, even more preferred, with a heptapeptide of the general formula (Va) P 1 -Ser(P 2 )-NM
- the heptapeptide of the general formula (V) is the heptapeptide (VI) H-Ser(tBu)-NMeTyr-D-Lys(Nic)-Leu-Lys(iPr,Boc)-Pro-D-AlaNH 2 (VI), or even more preferred, the heptapeptide (VIa) H-Ser(tBu)-NMeTyr-D-Asn-Leu-Lys(iPr,Boc)-Pro-D-AlaNH 2 (VIa)
- a particular advantage with the method of the invention is that a cheaper starting material, H-D-Pal-OH.2HCl, can be used instead of the ester H-Pal-OR.2HCl; the protective group of the starting material need not be removed. Therefore the synthesis of the invention is one step shorter and avoids that material is lost in the additional step.
- Another advantage is that the formation of impurities in the saponification step is avoided. The formation of such impurities is well known. For instance, the basic conditions at the ester hydrolysis step cause partial racemization of D-Pal.
- the other prior-art alternative of removing the ester group by catalytic hydrogenation in the case of allyl or benzyl ester groups) risks to cause a loss of Cl from 4ClPhe producing Phe. While allyl groups may be removed by still other reagents the full removal is difficult to control.
- Boc-D-4ClPhe-OSu Boc-D-4ClPhe-OH (299,75 g; 1,0 eq.) and HONSu (184,1 g; 1,6 eq.) are dissolved in 2-propanol (4,5 L). The mixture is cooled to 0° C. and DIC (164,1 g; 1.3 eq.) is added. The mixture is stirred for 16 h while warming to room temperature. The product is filtered of, washed with 2-propanol (1,5 L) and dried. Yield: 85%. HPLC purity: 98,8%.
- Boc-D-4ClPhe-D-3Pal-OH H-D-3Pal-OH, 2 HCl (251,1 g; 1,05 eq.) and Boc-D-4ClPhe-OSu (396,8 g; 1,0 eq.) are dissolved in DMSO (3,33 L) and NMM (318,8 g; 3,15 eq.) is added. The mixture is stirred for 16 h at room temperature. Water (17 L) is added and pH is adjusted to 4-4,5 which causes the product to precipitate. The mixture is filtered and the product is washed with water (3 ⁇ 5 L) to remove traces of DMSO, H-D-3Pal-OH and Boc-D-4ClPhe-OH. The product is dried. Yield: 80%. HPLC purity: 97,8%
- Boc-D-2Nal-OSu Boc-D-2Nal-OH (315,4 g; 1,0 eq.) is dissolved in 2-propanol (6,8 L) at ⁇ 10° C. and IBC (157 g; 1,15 eq.) and NMM (116 g; 1,15 eq.) is added. After stirring for 5-10 min a mixture of HONSu (230,1 g; 2,0 eq.) in 2-propanol (1,4 L) is added. Additional NMM (10,1 g; 0,1 eq.) is added. After half an hour water (0,82 L) is added to dissolve precipitated NMM ⁇ HCl. The product is isolated by filtration, washed with 2-propanol (1 L), and dried. Yield.: 90%. HPLC purity: 98,3%.
- Boc-D-4ClPhe-D-3Pal-OH (447,93 g; 1,0 eq.) is dissolved in a mixture of ethyl acetate (3,4 L), acetic acid (675 ml) and MSA (454 mL; 7,0 eq.) at 0° C. and kept at this temperature for two hours.
- TEA (1669 ml; 12 eq.) is added.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Endocrinology (AREA)
- Analytical Chemistry (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12/189,925 US8173770B2 (en) | 2001-12-29 | 2008-08-12 | Intermediates for LHRH antagonist synthesis, process for the production, and process for LHRH antagonist production |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0104463-5 | 2001-12-29 | ||
| SE0104463A SE0104463D0 (sv) | 2001-12-29 | 2001-12-29 | Mellanprodukter för syntes af LHRH-antagonister, sätt att framställa dem och sätt för framställning av LHRH-antagonister |
| PCT/IB2002/005583 WO2003055902A1 (en) | 2001-12-29 | 2002-12-23 | Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US12/189,925 Continuation US8173770B2 (en) | 2001-12-29 | 2008-08-12 | Intermediates for LHRH antagonist synthesis, process for the production, and process for LHRH antagonist production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US20050124788A1 true US20050124788A1 (en) | 2005-06-09 |
Family
ID=20286557
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US10/500,047 Abandoned US20050124788A1 (en) | 2001-12-29 | 2002-12-23 | Intermediates for lhrh antagonist synthesis, process for their production, and process for lhrh antagonist production |
| US12/189,925 Expired - Lifetime US8173770B2 (en) | 2001-12-29 | 2008-08-12 | Intermediates for LHRH antagonist synthesis, process for the production, and process for LHRH antagonist production |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US12/189,925 Expired - Lifetime US8173770B2 (en) | 2001-12-29 | 2008-08-12 | Intermediates for LHRH antagonist synthesis, process for the production, and process for LHRH antagonist production |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US20050124788A1 (enExample) |
| EP (2) | EP1465917B1 (enExample) |
| JP (1) | JP4272529B2 (enExample) |
| KR (1) | KR100844520B1 (enExample) |
| CN (1) | CN1304417C (enExample) |
| AT (2) | ATE371666T1 (enExample) |
| AU (1) | AU2002348749B2 (enExample) |
| CA (1) | CA2471723C (enExample) |
| CY (2) | CY1107580T1 (enExample) |
| DE (2) | DE60222189T2 (enExample) |
| DK (2) | DK1465917T3 (enExample) |
| ES (2) | ES2296050T3 (enExample) |
| IL (2) | IL162788A0 (enExample) |
| NO (1) | NO330129B1 (enExample) |
| NZ (1) | NZ534245A (enExample) |
| PT (2) | PT1630169E (enExample) |
| RU (1) | RU2307125C2 (enExample) |
| SE (1) | SE0104463D0 (enExample) |
| SI (1) | SI1630169T1 (enExample) |
| WO (1) | WO2003055902A1 (enExample) |
| ZA (1) | ZA200405136B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090234098A1 (en) * | 2004-03-09 | 2009-09-17 | Ajinomoto Co., Inc. | Method of preparing peptide |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101037472B (zh) * | 2006-03-14 | 2013-03-27 | 中国人民解放军军事医学科学院毒物药物研究所 | 具有低组胺释放作用的促黄体生成素释放激素拮抗剂 |
| JOP20090061B1 (ar) | 2008-02-11 | 2021-08-17 | Ferring Int Center Sa | طريقة معالجة سرطان البروستاتا بمضادات الهرمونات التناسلية GnRH |
| DK2632934T3 (en) | 2010-10-27 | 2017-01-23 | Ferring Bv | Process for the preparation of Degarelix and its intermediates |
| EP2447276A1 (en) | 2010-10-27 | 2012-05-02 | Ferring B.V. | Process for the manufacture of Degarelix and its intermediates |
| PL4512389T1 (pl) | 2012-06-01 | 2025-09-01 | Ferring B.V. | Produkt leczniczy degareliksu |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4098777A (en) * | 1977-03-14 | 1978-07-04 | Merck & Co., Inc. | Process for the preparation of pyroglutamyl-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn |
| US5322931A (en) * | 1990-07-24 | 1994-06-21 | Eastman Kodak Company | Process for synthesizing peptides - fragment condensation |
| US5710246A (en) * | 1996-03-19 | 1998-01-20 | Abbott Laboratories | Process for intermediates for the synthesis of LHRH antagonists |
| US6235734B1 (en) * | 1996-10-30 | 2001-05-22 | Pfizer Inc | Pyridone-fused azabicyclic- or cytisine derivatives, their preparation and their use in addiction therapy |
| US6699833B1 (en) * | 1996-12-11 | 2004-03-02 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained drug delivery |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SU1623166A1 (ru) * | 1989-04-03 | 1994-02-15 | Институт биоорганической химии АН БССР | Нейтропептиды, обладающие поведенческой активностью |
| US5225598A (en) * | 1990-03-30 | 1993-07-06 | Union Carbide Chemicals & Plastics Technology Corporation | Selective production of linear pentaethylenehexamine and hydroxyethyldiethylenetriamine |
| DE19941248A1 (de) | 1998-09-01 | 2000-03-02 | Asta Medica Ag | Peptide mit N-substituierten Glycingruppen sowie diese enthaltende Arzneimittel zur Behandlung hormonabhängiger Tumore |
-
2001
- 2001-12-29 SE SE0104463A patent/SE0104463D0/xx unknown
-
2002
- 2002-12-23 JP JP2003556432A patent/JP4272529B2/ja not_active Expired - Fee Related
- 2002-12-23 DE DE60222189T patent/DE60222189T2/de not_active Expired - Lifetime
- 2002-12-23 KR KR1020047010267A patent/KR100844520B1/ko not_active Expired - Fee Related
- 2002-12-23 US US10/500,047 patent/US20050124788A1/en not_active Abandoned
- 2002-12-23 PT PT05025717T patent/PT1630169E/pt unknown
- 2002-12-23 WO PCT/IB2002/005583 patent/WO2003055902A1/en not_active Ceased
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- 2002-12-23 AT AT05025717T patent/ATE371666T1/de active
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2004
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4098777A (en) * | 1977-03-14 | 1978-07-04 | Merck & Co., Inc. | Process for the preparation of pyroglutamyl-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn |
| US5322931A (en) * | 1990-07-24 | 1994-06-21 | Eastman Kodak Company | Process for synthesizing peptides - fragment condensation |
| US5710246A (en) * | 1996-03-19 | 1998-01-20 | Abbott Laboratories | Process for intermediates for the synthesis of LHRH antagonists |
| US6235734B1 (en) * | 1996-10-30 | 2001-05-22 | Pfizer Inc | Pyridone-fused azabicyclic- or cytisine derivatives, their preparation and their use in addiction therapy |
| US6699833B1 (en) * | 1996-12-11 | 2004-03-02 | Praecis Pharmaceuticals, Inc. | Pharmaceutical formulations for sustained drug delivery |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090234098A1 (en) * | 2004-03-09 | 2009-09-17 | Ajinomoto Co., Inc. | Method of preparing peptide |
| US7915224B2 (en) * | 2004-03-09 | 2011-03-29 | Ajinomoto Co., Inc. | Method of preparing peptide |
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